Process Validation Procedure

Objective

To lay down a procedure for Process Validation activity.

To verify all prerequisites have been met and the protocol information is complete.

Execution of defined activity with production and quality team during validation as per approved protocol.

Procedure

Definition:

Process Validation: The collection and evaluation of data from the process design stage through commercial production, which establishes scientific evidence that a process is capable of continuously delivering the finished product meeting its predetermined specifications and quality attributes.

Process Validation Protocol: Documented plan for testing a pharmaceutical product and process to confirm that the production process used to manufacture the product performs as intended. This includes a review of process variables and operational limitations as well as providing the sampling plan under actual use conditions.

Process Validation Report: A document in which the records, results and evaluation of a completed validation program are assembled and summarized. It may also contain proposals for the improvement of processes.

Critical quality attribute: A physical, chemical, biological or microbiological property or characteristic of materials or products that should be within an appropriate limit, range or distribution to ensure the desired product quality.

Critical process parameter: A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored and/ or controlled to ensure the process produces the desired quality.

Lifecycle: All phases in the life of product, from the initial development through marketing until the product’s discontinuation.

Concurrent Validation: Validation carried out during routine production of products intended for sale in exceptional circumstances when data from replicate production runs are unavailable because only a limited number of batches have been produced, batches are produced infrequently or batches are produced by a validated process that has been modified. Individual batches may be evaluated and released, based on thorough monitoring and testing of the batches.

Precaution:

Ensure the proper following of SOP during process validation execution activity

Refer MSDS/ PSDS of concern product before any activity.

Follow the instruction of safety while doing sampling, sample handling, manufacturing and analytical activity.

Follow cGMP and QMS while doing process validation.

Approach to process validation:

• Effective process validation contributes significantly to assuring product quality.
• Quality cannot be assured merely by in-process and finished - product testing. Quality, safety, and efficacy are designed or built into the product.
• Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.
• A risk based approach shall be used to identify and prioritize those process parameters and product quality attributes with the greatest potential to affect product quality.
• Before any batch(es) from the process validation study is commercially distributed for use by consumers, it should have ensured a high degree of assurance in the performance of the manufacturing process such that it will consistently produce products meeting those attributes relating to identity, strength, quality, purity, and potency.
• The assurance should be obtained from objective information and data from scientific experimental studies.
• Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions.
• A successful validation program depends upon information and knowledge from product and process development.
• After establishing and confirming the process, manufacturing technology must maintain the process in a state of control over the life of the process, even as materials, equipment, environment, personnel and manufacturing procedures change.
• General Considerations for Process Validation:
• An integrated team (including experts from various disciplines like engineering, safety, operation, FRD, Production, Warehouse, Quality control and Quality assurance) approach shall be followed to process validation.
• All studies shall be planned and conducted according to sound scientific principles, appropriately documented and approved in accordance with the established procedure appropriate for the stage of the lifecycle.
• Homogeneity within a batch and consistency between batches shall form goals of process validation activities.
• Stages of validation: Process validation involves a series of activities taking place over the life cycle of product and process. Based on the life cycle approach of process validation, process validation shall comprise of 3 stages:

Process design:

• Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records.
• The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
• Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway.
• In this stage the process knowledge and process understanding gained from the product development and execution of feasibility/ engineering, stretch study batch/ batches shall be used to define the commercial manufacturing process and the process control strategy.
• Additional process knowledge and process understanding can be gained from the process evaluation studies carried out at commercial scale.
• The challenging of process parameters shall be carried out during process evaluation studies (pre-validation/trial batches) to freeze the limits for different parameters. 
• The above activities and studies resulting in process understanding shall be documented for taking decisions about the process.
• This information is useful for the next two stages. All these type of deviation shall be reported in deviation part of report.
• The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation.
• The process design stage should form the basis for deciding the design space for the CPPs within which the batch manufacturing process should be capable of yielding a product with defined quality attributes.
• Process design shall cover design of experiments, process development, the manufacture of products for use in clinical trials and pilot‑scale batches.
• It shall cover aspects for the selection of materials, expected production variation, selection of production technology/ process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in‑process controls, tests, inspection and its suitability for the control strategy.
• This stage shall guide to determine critical quality attributer and critical process parameter.

Process qualification:

• During the process qualification stage the process design shall be evaluated to determine its capability of reproducible commercial manufacture.
• The PQ shall combine the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches.
• A successful PQ shall confirm the process design and demonstrate that the commercial manufacturing process performs as expected.
• The goal of validating any manufacturing process shall be to establish scientific evidence for reproducibility and consistency of process to deliver quality products.
• Need of process validation shall arise as a result of either the introduction of a new product or as a result of a change to an existing process.
• This stage shall comprise many elements like design and qualification of facility, equipment and utility, process performance qualification – protocol approval, execution and reporting.
• Materials, environmental controls, measuring systems, apparatus and methods shall be considered during this stage.
• Process qualification confirm that manufacturing at commercial stage shall not adversely affect the characteristics of the product and that a process that operates within the predefined specified parameters consistently produces a product which meets all its CQAs and control strategy requirements.

Continued process verification:

• This stage shall provide means to ensure that processes remain in a state of control during routine commercial manufacturing through an on-going programme to collect and evaluate product and process data related to quality, safety and efficacy.
• The data collected shall include relevant process trends and quality of incoming materials or components, in-process material, and finished products.
• The data shall be statistically trended and reviewed by trained personnel.
• All CQA’s of a product of each commercial batch shall be retrospectively monitored and trended annually as part of APQR.
• Data gathered during this stage shall be used to build an improvement and/ or optimize the process by altering some aspect of the process or product such as operating ranges, process, controls, component, or in process material characteristics.
• Any planned change to the validated process shall be addressed through a change control.
• This stage shall enable to monitor product quality of commercial batches after completion of process qualification stage. It shall be performed using trend analysis, process capability index calculation, continuous monitoring of critical process parameters, ongoing verification on annual basis.

Process Validation Policy:

• Process Validation shall be carried out for the following reasons:
• New products introduced by FRD Dept.
• Product transferred from other site & change in manufacturing process.
• Change in critical process parameters.
• Change to existing process/ formula/ raw materials/ batch size/ change in API vendor.
• Change in equipment, which has a direct impact on the manufacturing process.
• Change in production area (areas with equipment of different make/ capacity/ working principle).
• Major changes in the support system as identified by the validation committee members.
• As per the costumer & regulatory body requirement.
• Process Validation Pre-Requisite:
• The pre-requisite checklist shall form a part of PV protocol and attached with protocol.
• The design of the facility (Qualified facilities/ utilities/ equipment) shall support or appropriate for the manufacturing of the product.
• Risk assessment - A detailed risk assessment shall be carried out for product and process specific requirements to identify the studies to be performed.
• If there is more than one item of equipment, which is of the same type, process validation can be performed on any item, provided that the equipment qualification has demonstrated that the equipment is of similar design and operation.
• All analytical methods used for testing of the product have been validated.
• All related master documents like: MFR, BOM, BMR, BPR and FPS are available.
• All SOP’s related to the validation programmed are available.
• Trained personnel to carry out the validation.
• All the raw materials and primary packing materials are tested and released by QC.

Validation Procedure:

• Based on company’s decision to introduce a new product and considering the availability of raw & packing material, production shall be planned.
• Based on the process understanding and process knowledge gained from process design studies the CPP’s shall be monitored during process qualification study.
• All process validation activities shall be performed following a pre-approved protocol as per the requirements of product and its manufacturing technology.
• The process validation protocol shall be prepared in reference to the manufacturing process given in MFR/ MPR/ BMR/ BPR, analytical procedure as per Raw material/ Packing Material/ In process bulk/ Finished product.
• It shall contain manufacturing flow chart with detailed description of manufacturing procedure, critical parameters, drawing of sampling plan with respect to equipment involved during the process, in process test to be performed and its acceptance criteria.
• The manufacturing process shall be carried out stepwise as mentioned in the respective BMR and process validation protocol. During process validation of product following stages shall be considered for validation:
• Dispensing (Raw material and Packing material)
• Bulk manufacturing
• Bulk filling
• Crimping
• Propellant filling
• Packing and Packaging
• For new product, at least three initial consecutive batches shall be considered.
• For product transfer or having major changes at least three consecutive batches shall be considered after implementing the changes.
• Process Validation Protocol (PV Protocol): A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for the stage of process qualification. The protocol to contain following elements but not limited to:
• A title, protocol reference number, version, objective, scope, manufacturing formula, process description, validation team, critical process parameters, acceptance criteria, sampling plan for the analysis, sampling locations, signatures, dates, etc.
• The process validation plan should clearly define the validation strategy regarding the validation of the product at the packaging stage as applicable.
• The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs.
• The data to be collected and when and how it will be evaluated.
• Tests to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step.
• The sampling plan, including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. The samples shall be adequate to provide sufficient statistical confidence of quality (within batch and between batches).
• Acceptance criteria shall be provided in the product specific process validation protocol. Results and observation should comply with the acceptance criteria as provided in the validation protocol.
• Criteria and process performance indicators that allow for a science - and risk-based decision about the ability of the process to consistently produce quality products.
• The criteria shall include description of the statistical methods to be used in analysing all collected data.
• Provision for addressing deviations from expected conditions and handling of non-conforming data. Data should not be excluded from further consideration in terms of PQ without a documented, science-based justification.
• Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/ closures), if not previously accomplished.
• Status of the validation of analytical methods used in measuring the process, in-process materials, and the product.
• Review and approval of the protocol by appropriate departments.
• Process Validation Report (PV Report):
• A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol. This report should contain following elements:
• PV report shall include a concise description and summary of all studies performed.
• A detail result and discussion shall be the part of report which contains observations and data results obtained during the validation study and all the established process parameters shall be summarized in.
• The summarize data collection and analyse the data, as specified by the protocol.
• Evaluation of any unexpected observations and additional data not specified in the protocol. The yield observed during the execution of the validation batches should be captured and reviewed in the process validation report.
• A report of the validation shall be prepared by Validation team in computerized format but not limited to defined contents. Contents shall be changed as per requirement.
• Summary report detailing the critical validated product/machine parameter that is to be followed in routine production in future shall be prepared & conclusion drawn from it shall be mentioned in the report.
• Any exceptional conditions encountered during Process Validation shall be investigated and the appropriate course of action (justification, correction, or re-qualification studies) determined.
• Summarize and discuss all manufacturing nonconformance such as deviations, aberrant test results, or other information that has bearing on the validity of the process.
• Describe in sufficient detail any corrective actions or changes that should be made to existing procedures and controls.
• State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control. If not, the report should state what should be accomplished before such a conclusion can be reached.
• The conclusion should be based on a documented justification for the approval of the process, and release of lots produced by it to the market in consideration of the entire compilation of knowledge and information gained from the design stage through the process qualification stage.
• Include all appropriate department and Quality review and approvals.
• Failure of Process validation:
• If the PV batch fails to meet the acceptance criteria, the failure must be investigated as per root cause analysis procedure.
• Where the cause of the failure is not obvious it may be useful to use an appropriate investigation procedure to ensure all possible areas of potential failure are covered.
• Once the cause of PV failure has been identified the validation committee must agree in to which of the two main categories of failures it falls –
• Type -1: Where the failure can be attributed to occurrence which is non-intrinsic to the process, for example, equipment / utility failure or faulty raw material, then it can be agreed to complete the validation exercise substituting another batch for the one that failed.
• Type -2: Where the failure is attributed to the process failure or where the investigation is in-conclusive then the PV exercise is failed. Repeating the PV exercise shall be initiated after taking necessary corrective action and preventive action.

Criteria for Revalidation:

Revalidation after Changes – Whenever any new element in the manufacturing process, revalidation shall be introduced, impact assessment shall be performed to assess impact on product quality. Revalidation after changes shall be performed only when changes could have an impact on the product quality. The extent of re-validation shall be decided by the validation team. Revalidation shall be considered in following conditions:

Change in manufacturing formula/ procedure/ process

Change in raw material specification

Change in vendor source for API

Change in batch size

Change or modification in critical equipment

Major change in process parameter

Change in manufacturing facilities

Transfer of process or product to another site

As per recommendation from QMS (Change control/ deviation/ CAPA/ Risk management/ Market complaint/ APQR recommendation/ Self inspection)

Ongoing process verification of one batch of each product annually.

Process Validation Example Chart

Sampling for Validation:

• Sampling for process validation shall be performed as described in the product specific process validation protocol.
• As per protocol, quality assurance officer shall keep ready required sampling bags, identification labels and sampling tools.
• Quality assurance personnel shall do extensive sampling of the process stage wise as mentioned in the validation protocol.
• These samples shall be transferred to quality control department for analysis along with test request form and validation protocol.
• Test shall be performed at each stage during the process and results shall be compared with the acceptance criterion.
• After getting compliance report from quality control, production department shall start next process stage.

Note:

The Challenging (i.e. subjected   to   sampling   at different   time   limits) critical parameters (e.g. Mixing time, RPM, Dissolving Step, Homogenizing Speed) challenges at mixing stages in aerosol, Filling and machine speed shall be done in Process Validation)

In case validation of batches cannot be completed as per approved protocol due to less marketing requirement or is discontinued due to other justifiable reason then an ‘Interim Report’ shall be generated to give the status of various parameters tested during validation studies. However, process validation studies shall be deemed to be completed only on successful completion of three batches.

In cases where it is unlikely that second and/ or third batch of the product shall be manufactured for a period of time, generate interim reports on batch to batch basis till such time the process validation study is completed.

Sampling Plan

• Sampling shall be done by trained QA as per the sampling plan described in validation protocol.
• Validation data for all the critical parameters shall be collected & evaluated against predetermined set of limits.
• Any deviations or exceptions to approved protocols shall be noted, investigated and resolved and if required CAPA shall be initiated and shall be executed and closed.
• At the completion of validation, when all the deviations have been resolved and all acceptance criteria have been met and validated then the filled report shall be approved by Head QA.
• On completion of validation batches study, the respective batch master documents shall be revised to incorporate the changes in operational parameters if recommended in the Process Validation.
• Upon completion of the review by Production and Quality Control, recommendations shall be made on the extent of monitoring and the in-process controls necessary for routine production.
• If a change is proposed in any of the procedures, processes, or equipment, which may impact the quality then that, shall be done by following change control procedures.
• All changes must be formally requested, documented and accepted by the Validation Team and Quality Assurance department. The proposed changes shall be scientifically assessed and based on assessment need of re-validation or revision of document shall be determined.
• The change control associated with the introduction of the product shall be closed once the predetermined acceptance criteria have been met.
• After the confirmation that the process design is capable of reproducible commercial manufacture, continuous process verification of the process is carried out to assure that the process remains in a state of control.

Stability studies: Stability samples from the process validation batches shall be drawn and kept for stability study as described in the stability protocol.

Storage of Documents:

• Process Validation protocol and validation reports along with attached documents shall be filed and stored in Quality Assurance Department.
• Following statistical tools can be used for evaluation of CPP:
• Bar Chart
• Histogram
• Process Capability analysis and index
• Control Chart
• RSD (Relative Standard Deviation)